1887

Abstract

is one of the most dreaded opportunistic pathogens accounting for 10 % of hospital-acquired infections, with a 50 % mortality rate in chronically ill patients. The increased prevalence of drug-resistant isolates is a major cause of concern. Resistance in is mediated by various mechanisms, some of which are shared among different classes of antibiotics and which raise the possibility of cross-resistance. The goal of this study was to explore the effect of subinhibitory concentrations (SICs) of clinically relevant antibiotics and the role of a global antibiotic resistance and virulence regulator, AmpR, in developing cross-resistance. We investigated the induction of transient cross-resistance in PAO1 upon exposure to SICs of antibiotics. Pre-exposure to carbapenems, specifically imipenem, even at 3 ng ml, adversely affected the efficacy of clinically used penicillins and cephalosporins. The high β-lactam resistance was due to elevated expression of both and , encoding a chromosomal β-lactamase and its regulator, respectively. Differences in the susceptibility of and mutants suggested non-AmpC-mediated regulation of β-lactam resistance by AmpR. The increased susceptibility of in the absence of to various antibiotics upon SIC exposure suggests that AmpR plays a major role in the cross-resistance. AmpR was shown previously to be involved in resistance to quinolones by regulating MexEF–OprN efflux pump. The data here further indicate the role of AmpR in cross-resistance between quinolones and aminoglycosides. This was confirmed using quantitative PCR, where expression of the efflux pump was further induced by ciprofloxacin and tobramycin, its substrate and a non-substrate, respectively, in the absence of . The data presented here highlight the intricate cross-regulation of antibiotic resistance pathways at SICs of antibiotics and the need for careful assessment of the order of antibiotic regimens as this may have dire consequences. Targeting a global regulator such as AmpR that connects diverse pathways is a feasible therapeutic approach to combat pathogenesis.

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2014-04-01
2020-01-21
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